Retinal vein occlusion (RVO) is an obstruction of the retinal venous system by thrombus formation and may involve the central, hemi-central or branch retinal vein. The most common aetiological factor is compression by adjacent atherosclerotic retinal arteries. Other possible causes are external compression or disease of the vein wall e.g. vasculitis.

1. Retinal vein occlusion (RVO)
Dr RS Walpitagamage
Registrar in Ophthalmology
TH Kandy

2. Retinal vein occlusion (RVO)
• Retinal vein occlusion (RVO) is an obstruction of the retinal venous
system by thrombus formation and may involve the central, hemi-
central or branch retinal vein.
• The most common aetiological factor is compression by adjacent
atherosclerotic retinal arteries.
• Other possible causes are external compression or disease of the vein
wall e.g. vasculitis.
• Haematological pro thrombotic factors are thought to be important in
a minority.

3. Epidemiology of Retinal Vein Occlusion
• Retinal vein occlusions are a common cause of visual loss in the United
Kingdom, and are the second commonest cause of reduced vision due to
retinal vascular disease after diabetic retinopathy, with BRVO occurring 2 –
6 times as frequently as CRVO.
• US data reported in 2008 indicate a 15 year incidence of 500 new cases of
CRVO per 100,000 population and 1800 BRVO cases per 100,000
population.
• The incidence and prevalence of both these conditions increases with age.
• Australian data suggests that the prevalence of RVO is 0.7% for those
younger than 60 years, 1.2% for those 60 – 69 years, 2.1% for those 70 – 79
years and it increases to 4.6% in people aged 80 years or above.
• No gender or racial differences in prevalence of both these conditions have
been reported.

4. Aetiology and risk factors of RVO
• Age is the most important risk factor- over 50% of cases occur in patients older than 65
• Hypertension- 2/3 in age more than 50, 25% in younger
• Diabetes-15% in patients more than 50
• Hyperlipidaemia-1/3 or more, irrespective of age
• OCP- in young females
• Smoking
• Hyperhomocysteinaemia
• Blood coagulation disorders: high plasma viscosity such as due to leukaemia, myeloma,
Waldenstrom’s macroglobulinaemia, myelofibrosis, changes in protein C pathway, Factor
V Leiden.
• Systemic inflammatory disorders (Behçets disease, polyarteritis nodosa, sarcoidoisis,
Wegener’s Granulomatosis and Goodpasture’s Syndrome)
• Glaucoma
• Shorter axial length
• Retrobulbar external compression

5. Central retinal vein occlusion (CRVO)
• Central retinal vein and artery possess a common sheath at crossing
points posterior to lamina cribrosa so that atherosclerotic changes of
the artery may precipitate central retinal vein occlusion (CRVO)
• When venous occlusion occurs , elevation of venous and capillary
pressure with stagnant blood flow ensues, resulting retinal hypoxia,
damage to capillary endothelium, exudation and VEGF formation.
• It is classically characterised by disc oedema, increased dilatation and
tortuosity of all retinal veins, widespread deep and superficial
haemorrhages, cotton wool spots, retinal oedema and capillary non-
perfusion in all four quadrants of the retina.

6. Diagnosis CRVO
1. History- A sudden painless monocular fall in vision
2. Examination-
• VA- variable, depending on degree of ischaemia
• RAPD
• Gonioscopy- NVI-50% of eyes 2-4 months(100 day glaucoma)
• IOP
• Fundus-Severe tortuosity and engorgement of all branches,
extensive deep blot and flame shape haemorrhages, CWS,
hyperaemic disc oedema. NVE, disc collaterals

7. Diagnosis CRVO
3. Investigations
• FFA- shows a marked delay in arterio venous transit time. Areas of
capillary non perfusion. Assess foveal avascular zone and NVE
• OCT- Quantification of ME
• ERG- reduced b wave amplitude, reduced b:a ratio and prolonged b-
wave implicit time on the electroretinogram.

8. Severe tortuosity and
engorgement of all branches,
extensive deep blot and flame
shape haemorrhages, CWS,
hyperaemic disc oedema, ME

9. Ischaemic versus non-ischaemic CRVO
• CRVO can be broadly classified into ischaemic and non-ischaemic
types based on the area of capillary non-perfusion, and this
distinction is useful for clinical management.
• The Central Retinal Vein Occlusion study (CVOS) defined ischaemic
CRVO as fluorescein angiographic evidence of more than 10 disc areas
of capillary non-perfusion on seven-field fundus fluorescein
angiography.
• However, this definition may require revision to be appropriate for
the more recently adopted wideangle imaging.
• It is important that a clear distinction is made between foveal
ischaemia and an ischaemic CRVO (i.e. global retinal ischaemia).

10. Ischaemic CRVO is associated with one or
more of the following characteristics:-
1. Poor visual acuity (44% of eyes with vision of <6/60 develop rubiosis -
CVOS)
2. Relative afferent pupillary defect
3. Presence of multiple dark deep intra-retinal haemorrhages
4. Presence of multiple cotton wool spots
5. Degree of retinal vein dilatation and tortuosity
6. Fluorescein angiography showing greater than 10 disc areas of retinal
capillary non-perfusion on 7-field fluorescein angiography (CVOS)
7. Electrodiagnostic tests (ERG): reduced b wave amplitude, reduced b:a ratio
and prolonged b-wave implicit time on the electroretinogram.

11. • There is no evidence as to which combination of the above
characteristics best defines ischaemic CRVO.
• It is important to note that up to 30% of eyes with initially non-
ischaemic CRVO may convert to ischaemic subtype.
• This is usually heralded by further rapid visual deterioration and
requires additional assessment.
• The prevalence and incidence of ischaemic BRVO is not fully defined.
• Ischaemia involving the macula causes visual impairment.
• However, ischaemia may occur in peripheral areas of the retina and
result in retinal neovascularisation and vitreous haemorrhage.
• Neovascular glaucoma is rare in ischaemic BRVO.

12. Management of CRVO
• Treatment of risk factors (to be managed by patient’s
physician).
• Ophthalmic management

13. Medical Management in CRVO
The detection and management of associated systemic disease is
aimed at reducing the risk of future vascular occlusive events.
• Medical History
• BP measurement
• Serum glucose estimation
• Request laboratory investigations for FBC and ESR
Special tests may be required in some patients <50yrs, bilateral RVO,
family history of thrombosis- Thrombophilia screening, Autoantibodies,
homocysteine levels, carotid duplex ect.

14. Ophthalmological management of CRVO
• Treatment for Macular oedema
• Management of ischaemic central retinal vein occlusion and anterior
& posterior segment neovascularisation
• Management of established neovascular glaucoma

15. Treatment for Macular oedema- Laser
photocoagulation
• Macular oedema following CRVO results from leakage of perifoveal
capillaries into the macular area and is typically associated with visual
loss.
• There was no proven treatment for this condition until five years ago.
• The CVOS study failed to indicate benefit from grid treatment,
although a trend in favour of treatment was observed in younger
patients.
• There is also no evidence to suggest any benefit from a combination
of macular grid laser and intravitreal anti-VEGF or steroids for MO
secondary to CRVO.

16. Treatment for Macular oedema- Intravitreal
steroids
• Intravitreal triamcinolone acetonide (IVTA)
• Intravitreal dexamethasone

17. Intravitreal triamcinolone acetonide (IVTA)
• The rationale for the use of intravitreal triamcinolone acetonide
(IVTA) to treat MO is that corticosteroids reduce retinal capillary
permeability and inhibit the expression of the VEGF gene and the
metabolic pathway of VEGF.
• Evidence from the SCORE study indicates that it may produce
anatomical and functional improvement of MO related to CRVO but
the effects are short-lived.
• Repeated IVTA may not necessarily improve vision.

18. Intravitreal dexamethasone
• The rationale for the use of intravitreal dexamethasone to treat MO is
similar to that of IVTA, although dexamethasone has been shown to
be a more potent corticosteroid than IVTA.
• However, intravitreal dexamethasone, in its free form, has a short
half-life, which limits its clinical usefulness.
• A pre-filled applicator for single-use, sustained release with a
biodegradeable implant containing 0.7mg of dexamethasone
(Ozurdex, Allergan) was analysed in the GENEVA study programme.

19. • In this study , Ozurdex and an alternative dose of dexamethasone implant
(0.35mg) were compared to sham injection, in patients with CRVO and BRVO in
two parallel multicentre studies, the results and analyses of which were
published together as the GENEVA study.
• Re-treatment was possible six months after the first injection under pre-specified
re-treatment criteria.
• The two trials were analysed together and the primary outcome measure for all
patients was time to achieve a ≥ 15 letter gain.
• The percentage of eyes with ≥ 15 letter gain in BCVA was significantly higher in
both implant groups compared with sham at days 30 to 90 with a peak effect at
60 days.
• Subgroup analyses of the BRVO and CRVO subjects showed a significantly greater
number achieved ≥ 15 letter gain from 30 to 90 days than sham treated eyes.
• Subgroup analysis also revealed that sham-treated eyes in the BRVO subgroup
were more likely to improve spontaneously than sham-treated CRVO eyes,
corroborating previous natural history data from the CVOS and BVOS studies.

20. • In terms of safety, raised IOP peaked at month two (3.2% of patients
had an IOP>35 mmHg), but declined significantly by month three and
was close to 0% by month six, with 19% of patients requiring an IOP-
lowering agent at month six and 0.7% of patients requiring any IOP-
lowering surgical procedures.
• Similarly, rates of cataract progression were low with 7% progression
at month six, compared to 4% in the sham group.
• The results further indicate that eyes treated earlier had a better
chance of visual acuity gain, and that those treated later (i.e. controls
that were subsequently treated) never achieved the final visual acuity
gains of those treated promptly.

21. Treatment for Macular oedema-Anti-VEGF
Therapies
• Anti-VEGF agents are now a popular choice for treatment of MO due
to CRVO based on the fact that VEGF-A is a key cytokine that
mediates vascular leakage and causes MO in RVO. Intraocular VEGF
levels are significantly high in CRVO compared to controls.
1. Ranibizumab
2. Aflibercept
3. Bevacizumab

22. 1.Ranibizumab
• The pan-VEGF-A blocker, ranibizumab (LUCENTIS, Novartis) is EMA
approved and recommended by NICE (NICE TA238, May 2013) for the
treatment of visual impairment due to MO secondary to RVO.
• Ranibizumab is a humanized recombinant monoclonal antibody
fragment that selectively binds to human VEGF-A, and prevents it
from binding to its receptors.
• The licensed dose of ranibizumab is 0.5mg/0.05ml given as a single
intravitreal injection.
• The interval between two injections is at least 4 weeks.
• The pivotal Phase III randomized controlled trial that evaluated
ranibizumab (0.3mg and 0.5mg) in MO due to CRVO was the CRUISE
study

23. CRUISE study
• 60 Eligible patients with MO due to CRVO of less than 12 months
duration with BCVA of 20/40 to 20/320 and central macular thickness
of >250um on Stratus OCT were randomized 1:1:1 to receive monthly
injections of 0.3mg, 0.5mg or sham injections for a six month period
followed by a further six-month observation period in which all
patients in the study (including sham group) were monitored monthly
and received ranibizumab PRN if they met pre-specified re-treatment
criteria.
• The mean change from baseline BCVA at 12 months was 13.9 letters
(95% CI for mean 11-5 – 16.4) and 50.8% gained ≥ 15 letters from
baseline. 12.3% had a visual acuity of less than Snellen 20/200 at
month 12.

24. 2. Aflibercept
• The pan-VEGF-A, VEGF-B and placental growth factor (PlGF) blocker,
• aflibercept, continues to be evaluated in clinical trials which thus far
have shown promise, resulting in NICE issuing TA305 in February 2014
with regards to the use of aflibercept in CRVO.
• COPERNICUS was a phase three, prospective, randomized, double-
masked trial (n=187) comparing monthly intravitreal injection of
aflibercept 2mg (n=115) with sham (n=74) for the treatment of MO
secondary to CRVO
• Patients included were adults with MO secondary to CRVO with CRT
on OCT of >250 µm and ETDRS BCVA of 20/40 to 20/320. The primary
efficacy endpoint was the proportion of eyes with a gain of ≥15 ETDRS
letters in BCVA from baseline to week 24

25. COPERNICUS study
• At week 100, patients in the aflibercept treatment group showed a
mean change from baseline BCVA of 13.0 ETDRS letters, compared to
sham-treated eyes, which gained 1.5 letters
• The aflibercept group demonstrated a rapid reduction in CRT by week
24 and this was maintained to week 52
• Progression to ocular neovascularization during the first 52 weeks was
eliminated in the aflibercept group (0% vs. 6.8% in the sham
treatment group P=0.006). All neovascularization seen in the sham
group occurred in the anterior segment.

26. GALILEO study
• GALILEO study was a phase 3, randomised, double-masked trial comparing
intravitreal aflibercept with sham for MO secondary to CRVO.
• The study included treatment-naive patients (n=177) aged ≥18 years with
MO secondary to CRVO with CRT ≥250 µm and ETDRS BCVA of 20/40 to
20/320.
• Patients were randomized 3:2 to receive either aflibercept 2 mg or a sham
injection every four weeks for 24 weeks (and then treatment was
continued, masked but PRN, until week 76).
• There was no crossover in this study. The primary efficacy endpoint was the
proportion of patients who gained ≥15 letters in BCVA at week
24compared with baseline. Secondary endpoints included the change from
baseline to week 24 in BCVA and CRT
• Patients receiving aflibercept had a significantly greater mean change in
BCVA than the sham-treated patients at week 24 (18.0 vs 3.3 letters,
respectively; P<0.0001)

27. 3. Bevacizumab
• Currently, increasing short-term data support the fact that multiple
intravitreal bevacizumab injections reduce MO due to CRVO.
• The most common treatment regimen is two to three injections over
the first five to six months.
• However, further randomized, controlled trials are required to assess
long-term safety and efficacy of intravitreal bevacizumab.
• No recommendations on the use of intravitreal bevacizumab can be
made at this time.

28. Management of ischaemic central retinal vein
occlusion and anterior & posterior segment
neovascularisation
• Pan-retinal photocoagulation (PRP) remains the mainstay of treatment when iris
new vessels (NVI) or angle new vessels (NVA) and NVE are visible.
• Ischaemic CRVO should ideally be monitored monthly for new vessels of the iris
and/ or the angle.
• However, as this is not logistically possible in most centres, two to three monthly
reviews may be sufficient, unless there are particular risk factors.
• Pan-retinal photocoagulation is advocated at the earliest sign of iris or angle new
vessels.
• In circumstances when regular follow-up is impractical, prophylactic treatment
may be appropriate.
• Inhibitors of vascular endothelial growth factor (anti-VEGF agents) such as
ranibizumab, aflibercept and bevacizumab have anti-angiogenic properties and
may be used as adjuvants to pan-retinal photocoagulation in patients with
anterior segment neovascularisation secondary to ischaemic CRVO

29. Pan-retinal Photocoagulation Technique
• Pan-retinal photocoagulation for CRVO with NVI or NVA requires a
significant number of laser shots delivered adequately to cover the
ischaemic retina to ensure regression of NVI and /or NVA over time.
• Either single spot or multi-spot lasers may be used.
• Treatment is usually placed in the periphery avoiding areas of retinal
haemorrhage.
• Some cases require further treatment if the iris neovascularisation
fails to regress.

30. Management of established neovascular
glaucoma
• The aim of management of this condition in a blind eye is to keep the eye
pain free. This is usually achieved by topical steroids and atropine.
However, if the eye has any visual potential intraocular pressure should be
controlled with topical pressure-lowering agents or cyclo-ablative
procedures.
• In addition, regression of NVI and NVA seem to offer a long term chance of
maintaining ocular comfort.
• Intravitreal and intracameral anti-VEGF agents have been shown to cause
regression of iris new vessels and decrease angle obstruction.
• Comparative case series indicate that iris new vessels regress faster after
intravitreal bevacizumab with PRP than with PRP alone.
• The reports also suggest that bevacizumab may reduce the need for
surgical interventions and may also serve as a useful adjunct to filtering
surgery

31. Recommendations for Further Follow-up
• In eyes that have significant ischaemia (> 10DA non-perfusion) monthly
follow-up, after six months should be every three months for one year.
• In non-ischaemic eyes initial follow up every three months for six months is
advised.
• Subsequent follow-up for all patients will depend upon treatment given
and complications within the earlier period, but will not normally be
required after two years in uncomplicated cases.
• The development of disc collaterals +/- resolution of the CRVO indicates a
good outcome, and should lead to discharge from clinical supervision.
• However, data available on the treatment of MO with anti-VEGF agents
indicates that MO may recur for several years and therefore follow-up
beyond current recommendations may be required in a proportion of
patients to ensure long term maintenance of stabilized visual acuity gains

32. Experimental treatments
• McAllister and colleagues evaluated the effectiveness of a laser-induced
chorioretinal venous anastomosis as a treatment for non-ischemic CRVO
and observed that visual acuity improved significantly in eyes in which
successful anatomosis were created.
• However, chorioretinal anastomosis remains an experimental treatment.
• There are significant complications associated with the procedure eg
choroidal neovascularisation, retinal and subretinal fibrosis or traction, and
vitreous haemorrhage.
• Trials of other treatments such as radial optic neurotomy with pars plana
vitrectomy, and thrombolytic therapies are under way.
• These treatments, however, are only experimental at present and are,
therefore, not recommended except as part of clinical trials.

33. Branch retinal vein occlusion (BRVO)
• Branch retinal vein occlusion (BRVO) is caused by venous thrombosis
at an arteriovenous crossing where an artery and vein share a
common vascular sheath.
• It has similar features to CRVO except that they are confined to that
portion of the fundus drained by the affected vein.
• Hemi-retinal vein occlusion (HRVO) affects either the superior or
inferior retinal hemisphere, and the retinal haemorrhages are nearly
equal in two altitudinal quadrants (the nasal and temporal aspects) of
the involved hemisphere.
• The two main complications of RVO are macular oedema and retinal
ischaemia leading to iris and retinal neovascularisation.

34. Diagnosis of BRVO
1. History
• Symptoms: Sudden painless blurred vision , if central macula
involved.
• May be asymptomatic
2. Examination
• VA: Variable, Historically 50% of untreated eyes retain 6/12 or
better. But about a quarter only achieve 6/60 or worse.
• NVI and NVG much less common 2-3% at 3 years than CRVO
• Fundus: Supero temporal quadrant is most commonly affected.
Dilatation and tortuosity of the affected venous segment, with
flame shaped and dot /blot haemorrhages. The site of occlusion
may be identified as an AV crossing point.

35. Diagnosis of BRVO
3. Investigations
• FA: May be diagnostic in late subtle cases. Venous filling is delayed.
Demonstrate peripheral ischaemia and macular ischaemia-
capillary non perfusion ,staining of vessel wall, vessel ‘pruning’
• OCT: Quantification of macular oedema.

36. Management of BRVO
• Treatment of risk factors (to be managed by patient’s
physician).
• Ophthalmic management

37. Ophthalmological management of BRVO
• The diagnosis of BRVO is clinical, as described above.
• In doubtful cases, especially small BRVO, fluorescein angiography may
be indicated to confirm the diagnosis.
• Fluorescein angiography is particularly useful in determining the
extent of macular oedema and ischaemia, as well as peripheral
ischaemia.
• Macular oedema and neovascularisation of the retina or disc are the
two major complications that may require therapy.
• Retinal neovascularisation occurs in 36% of eyes with >5 DD and 62%
with >4DD area of non-perfusion.

38. Treatment for Macular oedema due to BRVO - Summery of Randomized
clinical trials

39. Treatment for Macular oedema due to BRVO - Summery of Randomized
clinical trials

40. Treatment of neovascularisation
• Disc or retinal neovascularisation is an indication for photocoagulation to
the ischaemic retina (sector photocoagulation), although available
evidence suggests that waiting until vitreous haemorrhage occurs before
laser treatment does not adversely affect the visual prognosis.
• New vessels occur only when there is at least a quadrant of capillary
closure and commonly after six months following the occlusion.
• Follow up visits at three to four monthly intervals are recommended in
patients with one quadrant or more retinal ischaemia.
• It is recommended that sector laser photocoagulation is applied once
retinal or optic disc neovascularisation occur.
• Fluorescein angiography is not usually necessary prior to laser because the
area of ischaemia is visible clinically.

41. Photocoagulation to the ischaemic retina
(sector photocoagulation)
• Photocoagulation for retinal neovascularisation in BRVO is applied to
the sector of retinal capillary closure.
• An adequate number of laser spots using a single spot or multisport
laser should be applied in the affected sector, one shot width apart
with sufficient energy to create a mild grey-white laser discoloration
of the retina.
• A quadrant usually requires at least 500 shots of 500μm diameter.

42. References
• https://www.rcophth.ac.uk/wp-content/uploads/2015/07/Retinal-
Vein-Occlusion-RVO-Guidelines-July-2015.pdf
• Kanski's Clinical Ophthalmology, International Edition 8th Edition

43. Thank You!

46. Treatment algorithm for NON-ISCHAEMIC
CRVO
• Baseline,Visual acuity measurement, colour fundus photographs and
fluorescein angiography, OCT,
• IOP, gonioscopy if ischaemic CRVO is suspected.
• If no iris or angle NV and there is OCT evidence of MO:
(a) If visual acuity is 6/96 or better, commence on either intravitreal anti-
VEGF therapy or Ozurdex implant
(b) If visual acuity is less than 6/96, the potential for significant improvement
in visual acuity is minimal and the risk of ocular neovascularisation is
high.However, eyes with VA< 6/96 may be offered treatment as some of
these eyes may respond. The patients should be watched for NVI/NVA
(c)If visual acuity is better than 6/12, it is reasonable to observe the patient
for spontaneous resolution as per the judgment of the treating
ophthalmologist.

47. Choice of agent
• Ranibizumab and aflibercept are the two anti-VEGF agents
recommended by NICE for MO due to CRVO. Ozurdex, a
dexamathasone implant is also recommended by NICE for this
condition.
• There is no visual acuity or central macular thickness restriction in the
commencement of treatment with any of these agents.
• Although any of these drugs may be used as first line for this
condition, anti-VEGF is preferred in eyes with a previous history of
glaucoma and younger patients who are phakic.
• Ozurdex may be a better choice in patients with recent cardiovascular
events and in those who do not favour monthly injections.

48. Re-treatment
• At each follow-up visit, visual acuity, macular thickness and IOP should be
assessed and the presence of NVI/NVA assessed.
• If ranibizumab is the first line of treatment, monthly intravitreal injections
are continued until maximum visual acuity is achieved, which is defined as
stable visual acuity for three consecutive monthly assessments while on
ranibizumab therapy.
• If no improvement in visual acuity over the course of the first three
injections is observed, cessation of treatment may be considered and is
recommended after six injections.
• Patients who achieve visual acuity stability should be monitored monthly
and treatment with ranibizumab is resumed when monitoring indicates
loss of visual acuity due to MO secondary to CRVO.
• Monthly injections should then be administered again until stable visual
acuity is reached for three consecutive monthly assessments (implying a
minimum of two injections).
• The interval between two doses should not be shorter than one month.

49. Treatment algorithm for ISCHAEMIC CRVO
• If iris or angle neovascularisation occurs and the anterior chamber
angle is open Urgent PRP is recommended and with review at two
weeks initially and then less frequently as regression occurs.
• PRP plus intravitreal bevacizumab (off license) can be repeated if
NVI/NVA persist.
• If iris or angle NV are present with a closed angle and raised
intraocular pressure Urgent PRP is recommended with cyclodiode
laser therapy / tube shunt surgery. The latter is preferable if the angle
closure is established.

50. Treatment algorithm NON-ISCHAEMIC BRVO
Baseline
1. If VA better than 6/12, it is reasonable to regularly observe progress
for three months.
2. If VA is 6/12 or worse with macular odema and haemorrhages are
not masking fovea:
a) FFA is recommended to assess foveal integrity
b) If no macular ischaemia is identified, regularly observe for three
months if macular
oedema is mild and in opinion of clinician likely to spontaneously
improve (30% chance)

51. c) If mild to moderate macular ischaemia is present consider treatment
with
ranibizumab or Ozurdex if spontaneous improvement is unlikely
d) If severe macular ischaemia is present — no treatment is
recommended, and regularly observe for NV formation
3. If VA 6/12 or worse + macular oedema and haemorrhages are
masking macula
a) Monthly ranibizumab or baseline Ozurdex for three months.
b) Perform FFA at 3 months to assess foveal integrity
c) If severe macular ischaemia is found to be present at three months,
no treatment will likely be beneficial and further therapy should be
carefully considered

52. Treatment algorithm ISCHAEMIC BRVO
a) Watch carefully for NV
b) If NVE — consider sector laser photocoagulation applied to all
ischaemic quadrants.
Intravitreal bevacizumab (off-license) may also be given in combination
with laser.
c) Follow-up at three monthly intervals for up to 24 months.